Sugar derivatives of macrolides

- Pfizer Inc.

This invention relates to the saccharide derivatives of macrocyclic compounds useful for the treatment of resistance to transplantion, autoimmune disease and fungal diseases.

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Claims

1. A compound of the formula ##STR28## or a pharmaceutically acceptable salt thereof; wherein n is 1 or 2;

the dotted line represents an optional double bond in the case where R.sup.2 is H;
A and B are taken separately and are each independently H or OH, or A and B are taken together and form.dbd.O;
R.sup.2 is H, (C.sub.2 -C.sub.5)alkanoyloxy or --OR.sup.0;
R.sup.3 is (C.sub.1 to C.sub.3)alkyl or allyl;
R.sup.1 and R.sup.0 are each H, ##STR29## R.sup.4 is, for each occurrence, independently --CO.sub.2 R.sup.8, --CO.sub.2 H, --CH.sub.2 OH, H, --CH.sub.3, --CONH.sub.2, --CONHR.sup.8, --CONR.sub.2.sup.8, --CH.sub.2 OCOR.sup.8, --CH.sub.2 OCO.sub.2 R.sup.8, --CH.sub.2 OCONHR.sup.8, --CH.sub.2 OCONR.sub.2.sup.8 or --CH.sub.2 OR.sup.8;
R.sup.5, R.sup.6 and R.sup.7 are, for each occurrence, independently (C.sub.1 to C.sub.4) alkoxy, benzyloxy, --OH, --OCOR.sup.8, --OCO.sub.2 R.sup.8 or --OSi(R.sup.9).sub.3;
R.sup.8 is (C.sub.1 to C.sub.6)alkyl, (C.sub.3 to C.sub.6)cycloalkyl, allyl, pyridyl, thienyl, benzyl, benzyl substituted with one to five halogen atoms, --OH groups, or (C.sub.1 to C.sub.4)alkoxy groups, phenyl or phenyl substituted with one to five halogen atoms, --OH groups or (C.sub.1 to C.sub.4) alkoxy groups; and
R.sup.9 is, for each occurrence, independently (C.sub.1 to C.sub.4)alkyl, phenyl or benzyl; provided that
when R' is H, then R.sup.2 is --OR.sup.0 and R.sup.0 is ##STR30##

2. A compound according to claim 1 wherein the dotted line represents no bond and R.sup.2 is --OH.

3. A compound according to claim 2 wherein n is 2 and A and B are taken together and form.dbd.O.

4. A compound according to claim 3 wherein R.sup.3 is methyl, ethyl or allyl.

5. A compound according to claim 4 wherein R.sup.3 is ethyl.

6. A compound according to claim 5 wherein R.sup.1 is ##STR31##

7. A compound according to claim 6 wherein R.sup.4 is --CH.sub.2 OH, --CH.sub.3, --CH.sub.2 OCOCH.sub.3, --CH.sub.2 OCOCH.sub.2 C.sub.6 H.sub.3, or --CO.sub.2 CH.sub.3; and R.sup.5, R.sup.6 and R.sup.7 are each, independently, --OH, OCOCH.sub.3 or --OCOCH.sub.2 C.sub.6 H.sub.5.

8. A compound according to claim 7 wherein R.sup.1 is ##STR32##

9. The compound according to claim 8 wherein R.sup.4 is --CH.sub.3, R.sup.5 is --OCOCH.sub.3, R.sup.6 is --OCOCH.sub.3 and R.sup.7 is --OCOCH.sub.3.

10. The compound according to claim 8 wherein R.sup.4 is --CH.sub.3, R.sup.5 is --OH, R.sup.6 is --OH and R.sup.7 is --OH.

11. A compound according to claim 7 wherein R.sup.1 is ##STR33##

12. The compound according to claim 11 wherein R.sup.4 is --CH.sub.2 OCOCH.sub.3 and R.sup.5, R.sup.6 and R.sup.7 are each --OCOCH.sub.3.

13. The compound according to claim 11 wherein R.sup.4 is --CH.sub.2 OCOCH.sub.3 and R.sup.5, R.sup.6 and R.sup.7 are each --OH.

14. A compound according to claim 1 wherein n is 2; A and B are taken separately and are each H; the dotted line represents no bond; R.sup.2 is --OH and R.sup.3 is ethyl.

15. The compound according to claim 14 wherein R.sup.1 is ##STR34##

16. A compound according to claim 1 wherein n is 2; A and B are taken together and form.dbd.O; the dotted line represents no bond; R.sup.2 is OR.sup.0; R.sup.3 is ethyl and R.sup.0 and R.sup.1 are each ##STR35##

17. A method for treating resistance to transplantation in a mammal in need of such treatment comprising administering to said mammal a resistance to transplantation treating effective amount of a compound according to claim 1 or a pharmaceutically-acceptable salt thereof.

18. A method for treating autoimmune disease in a mammal in need of such treatment comprising administering to said mammal an autoimmune disease treating effective amount of a compound according to claim 1 or a pharmaceutically-acceptable salt thereof.

19. A method for treating fungal diseases in a mammal in need of such treatment comprising administering to said mammal a fungal disease treating effective amount of a compound according to claim 1 or a pharmaceutically-acceptable salt thereof.

20. A pharmaceutical composition comprising a resistance to transplantation treating effective amount of a compound of claim 1 and a pharmaceutically-acceptable carrier.

21. A pharmaceutical composition comprising an autoimmune disease treating effective amount of a compound of claim 1 and a pharmaceutically-acceptable carrier.

22. A pharmaceutical composition comprising a fungal disease treating effective amount of a compound of claim 1 and a pharmaceutically-acceptable carrier.

Referenced Cited
U.S. Patent Documents
4046878 September 6, 1977 Patelli et al.
4894366 January 16, 1990 Okuhara et al.
Foreign Patent Documents
0323042 July 1989 EPX
0428365 May 1991 EPX
0466365 January 1992 EPX
WO9102736 March 1991 WOX
Patent History
Patent number: 5747465
Type: Grant
Filed: Aug 8, 1994
Date of Patent: May 5, 1998
Assignee: Pfizer Inc. (New York, NY)
Inventor: Kevin Koch (Mystic, CT)
Primary Examiner: Elli Peselev
Attorneys: Peter C. Richardson, Gregg C. Benson
Application Number: 8/284,504
Classifications
Current U.S. Class: The Hetero Ring Has 8 Or More Ring Carbons (514/28); Propionate, Butyrate Or Isobutyrate Containing (536/65); Acetic Acid Utilized In Pretreatment (536/71); 536/181
International Classification: A61K 3170; C07H 1708;